WO2017143134A1 - Modulateurs de fxr et leurs procédés d'utilisation - Google Patents

Modulateurs de fxr et leurs procédés d'utilisation Download PDF

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Publication number
WO2017143134A1
WO2017143134A1 PCT/US2017/018292 US2017018292W WO2017143134A1 WO 2017143134 A1 WO2017143134 A1 WO 2017143134A1 US 2017018292 W US2017018292 W US 2017018292W WO 2017143134 A1 WO2017143134 A1 WO 2017143134A1
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Prior art keywords
compound
dimethyl
alkyl
pyrrolo
carboxylate
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PCT/US2017/018292
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English (en)
Inventor
Guangyi Wang
Leonid Beigelman
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Alios Biopharma, Inc.
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Publication of WO2017143134A1 publication Critical patent/WO2017143134A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the farnesoid X receptor (FXR) is known to be expressed in the liver, kidney, and intestines. Lundquist, IV, J.T. et al. J. Med. Chem. 2010, 53, 1774-1787.
  • FXR's native ligands are bile acids, for example, chenodeoxycholic acid. Id.
  • activation of FXR by FXR agonists results in beneficial metabolic effects, for example, glucose lowering, insulin sensitization, triglyceride lowering, and cholesterol lowering.
  • FXR agonists have also been shown to have hepatoprotective effects by preventing lipid accumulation, reducing fibrosis, and reducing inflammation in the liver. Abel, U. et al. at
  • modulators i.e., agonists or partial agonists
  • FXR modulators of FXR
  • modulators of FXR include, for example, the treatment of dyslipidemia, liver disease, diabetes, diabetic nephropathy, vitamin-D-related diseases, drug-induced side effects, hepatitis, inflammatory bowel disease, hypertriglyceridemia, gallstones, nonalcoholic steatohepatitis, atherosclerosis, and Primary Billiary Cirrhosis. Lundquist, IV, J.T. et al. at 1774; Richter, H.G.F. et al. at 1134; Abel, U. et al. at 4911. As such, modulators of FXR are needed.
  • R 1 is H, halogen, -CN, Ci- 6 alkyl, C 3 - 6 cycloalkyl, -OCi- 6 alkyl, or -OC 3 - 6 cycloalkyl
  • R 2 is halogen, -CN, Ci- 6 alkyl, C 3 - 6 cycloalkyl, -OCi- 6 alkyl, or -OC 3 - 6 cycloalkyl
  • R 3 is Ci- 6 alkyl or C 3 - 6 cycloalkyl
  • R 4 and R 5 are each independently H or Ci- 6 alkyl; at least one of A, B, D, and E is N and the others are CH or CR 6
  • R 6 is halogen, -CN, OH, -OCi -6 alkyl, or Ci -6 alkyl
  • Z is O, -NH-, or -N(Ci-6alkyl)-
  • G is CH, or N
  • J is C, CH, or N
  • compositions and methods which are, for clarity, described herein in the context of separate aspects, may also be provided in combination in a single aspect. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any
  • alkyl when used alone or as part of a substituent group, refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms (“C 1-12 "), preferably 1 to 6 carbons atoms (“Ci-6”), in the chain.
  • alkyl groups include methyl (Me, Cialkyl) ethyl (Et, C2alkyl), n-propyl (C 3 alkyl), isopropyl (C 3 alkyl), butyl (C4alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (Csalkyl), isopentyl (Csalkyl), tert-pentyl (Csalkyl), hexyl (Cealkyl), isohexyl (Cealkyl), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • cycloalkyl when used alone or as part of a substituent group, refers to an alkyl group having at least one ring.
  • the cycloalkyl groups of the disclosure have from 3 to 6 carbon atoms ("C3-6").
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-cyclopropyl, methyl-cyclobutyl, methyl- cyclopentyl, and the like.
  • C1-3 includes C 1-3 , C 1-2 ,
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • halo represents chloro, fluoro, bromo, or iodo.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, gly colic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
  • ethanesulfonic acid 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l -carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum i
  • hydrochloride hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the disclosure is administered.
  • a “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • Subject includes humans.
  • the terms “human,” “patient,” and “subj ect” are used interchangeably herein.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • treatment refers to delaying the onset of the disease or disorder.
  • isotopic variant refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more nonradioactive isotopes, such as for example, deuterium ( 2 H or D), carbon-13 ( 1 C), nitrogen-15 ( 15 N), or the like.
  • any hydrogen may be 2 H/D
  • any carbon may be 1 C
  • any nitrogen may be 15 N
  • the disclosure may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • Radiolabeled compounds of the disclosure can be used in diagnostic methods such as Single- photon emission computed tomography (SPECT).
  • SPECT Single- photon emission computed tomography
  • the radioactive isotopes tritium, i.e. H, and carbon-14, i.e. 14 C, are particularly useful for their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting
  • isotopes such as C, F, O and N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • isotopic variants of the compounds of the disclosure are intended to be encompassed within the scope of the disclosure. It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers,” for example, diastereomers and enantiomers.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.”
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. , as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture.”
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • tautomerism is the acid-and nitro-forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)-or ( ⁇ -stereoisomers or as mixtures thereof.
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • any open valency appearing on a carbon, oxygen, or nitrogen atom in any structure described herein indicates the presence of a hydrogen atom.
  • a chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, separately or as a mixture, are encompassed by that structure.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
  • R 1 is H, halogen, -CN, Ci- 6 alkyl, C 3 - 6 cycloalkyl, -OCi- 6 alkyl, or -OC 3 - 6 cycloalkyl.
  • R 1 can be attached at any position of the phenyl ring to which it is attached.
  • R 1 is H.
  • R 1 is halogen, i.e., F, CI, Br, or I.
  • R 1 is halogen
  • the halogen is preferably F or CI.
  • R 1 is -CN.
  • R 1 is Ci- 6 alkyl, for example, Cialkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, Csalkyl, or Cealkyl.
  • R 1 is C 3 - 6 cycloalkyl, for example, C 3 cycloalkyl, C 4 cycloalkyl, CiCycloalkyl, or Cecycloalkyl.
  • R 1 is -OCi- 6 alkyl, for example, -OCialkyl, -OC 2 alkyl, -OC 3 alkyl, -OC 4 alkyl, -OC 5 alkyl, or -OC 6 alkyl. In other aspects, R 1 is
  • -OC 3 - 6 cycloalkyl for example, -OC 3 cycloalkyl, -OC 4 cycloalkyl, -OCscycloalkyl, or
  • R 2 is halogen, -CN, Ci- 6 alkyl, C 3 - 6 cycloalkyl, -OCi- 6 alkyl, or -OC 3 - 6 cycloalkyl.
  • R 2 is halogen, i.e., F, CI, Br, or I.
  • the halogen is preferably F or CI.
  • R 2 is
  • R 2 is Ci- 6 alkyl, for example, Cialkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, Csalkyl, or Cealkyl.
  • R 2 is C 3 - 6 cycloalkyl, for example, C 3 cycloalkyl, C 4 cycloalkyl, CiCycloalkyl, or Cecycloalkyl.
  • R 2 is -OCi- 6 alkyl, for example, -OCialkyl, -OC 2 alkyl, -OC 3 alkyl, -OC 4 alkyl, -OC 5 alkyl, or -OC 6 alkyl.
  • R 2 is -OC 3 - 6 cycloalkyl, for example, -OC 3 cycloalkyl, -OC 4 cycloalkyl, -OCscycloalkyl, or
  • R 1 is H and R 2 is F or CI. In some preferred embodiments of the disclosure, R 1 is H and R 2 is F. In other preferred embodiments, R 1 is H and R 2 is CI. In some preferred embodiments of the disclosure, R 1 is F and R 2 is F. In other embodiments, R 1 is CI and R 2 is CI.
  • R 3 is Ci- 6 alkyl or C 3 - 6 cycloalkyl.
  • R 3 is Ci_ 6 alkyl, for example, Cialkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, Csalkyl, or Cealkyl.
  • R 3 is C 3 - 6 cycloalkyl, for example, C 3 cycloalkyl, C 4 cycloalkyl, Cscycloalkyl, or Cecycloalkyl.
  • R 3 is C 2 alkyl (ethyl).
  • R 3 is C 3 alkyl (propyl or isopropyl), with isopropyl being more preferred.
  • R 4 and R 5 are each independently H or Ci- 6 alkyl.
  • R 4 is H and R 5 is Ci- 6 alkyl, for example, Cialkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, Csalkyl, or Cealkyl.
  • R 4 is Ci- 6 alkyl, for example, Cialkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, Cialkyl, or Cealkyl
  • R 5 is H.
  • R 4 and R 5 are each independently Ci- 6 alkyl, that is, R 4 and R 5 are each independently Cialkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, Csalkyl, or Cealkyl. In some embodiments, R 4 and R 5 are each H. In preferred embodiments, R 4 and R 5 are each methyl (Cialkyl).
  • At least one of A, B, D, and E is N and the others are independently CH or CR 6 , wherein R 6 is halogen, -CN, OH, -OCi -6 alkyl, or Ci -6 alkyl.
  • R 6 is halogen, -CN, OH, -OCi -6 alkyl, or Ci -6 alkyl.
  • at least one of A, B, D, and E is N and the others are CH.
  • at least one of A, B, D, and E is N, one of the others is CR 6 , and the remaining are CH.
  • R 6 is preferably -OH or -OCi- 6 alkyl, for example, - OCi -6 alkyl, for example, -OCialkyl, -OC 2 alkyl, -OC 3 alkyl, -OC 4 alkyl, -OC 5 alkyl, or -OC 6 alkyl.
  • R 6 is halogen, preferably F or CI.
  • R 6 is -CN.
  • R 6 is Ci- 6 alkyl, for example, Cialkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, Csalkyl, or Cealkyl.
  • A is N and B, D, and E are independently CH or CR 6 . In other aspects, A is N and B, D, and E are each CH. In some aspects, A is N, one of B, D, and E is CR 6 and the others are CH. In other aspects, A is N, two of B, D, and E are independently CR 6 , and the other is CH. In yet other aspects, A is N and each of B, D, and E is independently CR 6 . In still other aspects, A is N, B is CR , D is CH, and E is CH. In other aspects, A is N, B is CH, D is CR , and E is CH. In yet other aspects, A is N, B is CH, D is CR , and E is CH. In yet other aspects, A is N, B is CH, D is CH, and E is CR 6 .
  • B is N and A, D, and E are independently CH or CR 6 . In other aspects, B is N and A, D, and E are each CH. In some aspects, B is N, one of A, D, and E is CR 6 and the others are CH. In other aspects, B is N, two of A, D, and E are independently CR 6 , and the other is CH. In yet other aspects, B is N and each of A, D, and E is independently CR 6 . In still other aspects, B is N, A is CR 6 , D is CH, and E is CH. In other aspects, B is N, A is CH, D is CR 6 , and E is CH. In yet other aspects, B is N, A is CH, D is CR 6 , and E is CH. In yet other aspects, B is N, A is CH, D is CH, and E is CR 6 .
  • D is N and A, B, and E are independently CH or CR 6 . In other aspects, D is N and A, B, and E are each CH. In some aspects, D is N, one of A, B, and E is CR 6 and the others are CH. In other aspects, D is N, two of A, B, and E are independently CR 6 , and the other is CH. In yet other aspects, D is N and each of A, B, and E is independently CR 6 . In still other aspects, D is N, A is CR 6 , B is CH, and E is CH. In other aspects, D is N, A is CH, B is CR 6 , and E is CH. In yet other aspects, D is N, A is CH, B is CH, and E is CR 6 . In yet other aspects, D is N, A is CH, B is CH, and E is CR 6 .
  • E is N and A, B, and D are independently CH or CR 6 . In other aspects, E is N and A, B, and D are each CH. In some aspects, E is N, one of A, B, and D is CR 6 and the others are CH. In other aspects, E is N, two of A, B, and D are independently CR 6 , and the other is CH. In yet other aspects, E is N and each of A, B, and D is independently CR 6 . In still other aspects, E is N, A is CR 6 , B is CH, and D is CH. In other aspects, E is N, A is CH, B is CR 6 , and D is CH. In yet other aspects, E is N, A is CH, B is CH, and D is CR 6 .
  • Z is O, -NH-, or -N(Ci-6alkyl)-.
  • Z is O.
  • Z is -NH-.
  • Z is -N(Ci- 6 alkyl)-, for example, - N(Cialkyl)-, -N(C 2 alkyl)-, -N(C 3 alkyl)-, -N(C 4 alkyl)-, -N(C 5 alkyl)-, or -N(C 6 alkyl)-.
  • G is CH or N. In some aspects, G is CH. In other aspects, G is N.
  • the compound of formula I is a compound of formula I-A:
  • the compound of formula I is a compound of formula I-B:
  • the compound of formula I is a compound of formula I-C:
  • the compound of formula I is a compound of formula I-D:
  • the disclosure also relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by
  • FXR Famesoid X Receptor
  • the disclosure also relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by Farnesoid X Receptor (FXR).
  • FXR Farnesoid X Receptor
  • Compounds of the disclosure are FXR agonists or FXR partial agonists.
  • the disclosed methods are accomplished by administering to the subject a compound of the disclosure in an amount sufficient to modulate FXR.
  • the compounds described herein are useful in the treatment of chronic cholestatic conditions, for example, Primary Biliary Cirrhosis (PBC) or Primary Sclerosing Cholangitis (PSC).
  • PBC Primary Biliary Cirrhosis
  • PSC Primary Sclerosing Cholangitis
  • the compounds described herein are also useful in the treatment of progressive familial intrahepatic cholestasis (PFIC), alcohol-induced cirrhosis and associated cholestasis, and liver fibrosis.
  • PFIC progressive familial intrahepatic cholestasis
  • alcohol-induced cirrhosis and associated cholestasis and liver fibrosis.
  • the compounds of the disclosure can be used to treat liver steatosis and associated syndromes, for example, non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the compounds of the disclosure can be used to treat cholestatic and/or fibrotic effects associated with cirrhosis (alcohol-induced cirrhosis) or viral hepatitis.
  • the compounds described herein are useful in the treatment of gallstones, for example, to prevent cholesterol gallstone formation or to prevent re-formation of gallstones after surgical removal or lithotripsy.
  • the compounds described herein are useful in reducing serum triglycerides and/or reducing total serum cholesterol.
  • the compounds described herein can be used to lower total cholesterol level, lower LDL cholesterol levels, lower VLDL cholesterol levels, and raise HDL cholesterol levels, and/or lower triglyceride levels.
  • the compounds described herein can also be used to treat dyslipidemia.
  • the compounds of the disclosure can be used to treat lipid and lipoprotein disorders, for example, hypercholesterolemia, hypertriglyceridemia, and artherosclerosis. Hanniman et al. J. Lipid Res. 2005, 46(12), 2595-2604.
  • the compounds of the disclosure can be used to treat cardiovascular disorders, for example, acute myocardial infarction, acute stroke, or thrombosis.
  • the compounds described herein are useful in improving insulin sensitivity and glucose tolerance.
  • the compounds described herein are also useful in the treatment of metabolic disorders, for example, type II diabetes and complications of diabetes (e.g., diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, peripheral arterial occlusive disease).
  • Compounds of the disclosure are useful in treating cancer, for example, breast cancer, colon cancer, or prostate cancer.
  • the compounds described herein are useful in treating
  • gastrointestinal conditions associated with a reduced uptake of dietary fat and fat-soluble dietary vitamins e.g., vitamin D
  • vitamins e.g., vitamin D
  • compound of the disclosure are useful in treating inflammatory bowel disorders such as, for example, Crohn's disease or colitis ulcerosa. Inagaki et al, Proc. Natl. Acad. Sci. USA. 2006, 103(10), 3920-3905.
  • compounds of the disclosure are useful in treating hepatitis B virus (HBV). See, e.g., WO 2015/036442.
  • an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in patients in need of such treatment for the designated disease, disorder, or condition.
  • Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID).
  • a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.
  • the compounds of the disclosure may be used in combination with additional active ingredients in the treatment of the above conditions.
  • the additional active ingredients may be co-administered separately with a compound of the disclosure or included with such an agent in a pharmaceutical composition according to the disclosure.
  • additional active ingredients are those that are known or discovered to be effective in the treatment of any of the diseases or disorders described herein.
  • the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the disclosure), decrease one or more side effects, or decrease the required dose of the active agent according to the disclosure.
  • a pharmaceutical composition of the disclosure comprises: (a) an effective amount of at least one compound in accordance with the disclosure; and (b) a pharmaceutically acceptable excipient.
  • compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art.
  • the compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
  • the preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.
  • the compositions are formulated for intravenous infusion, topical administration, or oral administration.
  • the compounds of the disclosure can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension.
  • the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily.
  • a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.
  • Oral tablets may include a compound according to the disclosure mixed with
  • inert diluents such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • compounds of the disclosure may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the compound of the disclosure with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain:
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like
  • non-aqueous vehicles e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water
  • preservatives for example, methyl or propyl p-hydroxybenzoate or sorbic acid
  • wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • compositions may be formulated for rectal administration as a suppository.
  • parenteral use including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an inj ectable formulation.
  • Illustrative infusion doses may range from about 1 to 1000 .mu.g/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1 % to about 10% of drug to vehicle.
  • a pharmaceutical carrier for topical administration, may be mixed with a pharmaceutical carrier at a concentration of about 0.1 % to about 10% of drug to vehicle.
  • Another mode of administering the compounds of the disclosure may utilize a patch formulation to affect transdermal delivery.
  • Compounds of the disclosure may alternatively be administered in methods of this disclosure by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
  • Step 4 2-methyl-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolor2.3-blpyridin-3- vDpropanenitrile.
  • 2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridin-3-yl)acetonitrile 7 g, 24.35 mmol
  • THF 50 mL
  • LiHMDS (1 M, 97.4 mL
  • the mixture was stirred at -78 °C for 60 mins, and Mel (14.52 g, 102.27 mmol) was added to the resulting mixture at -78 °C and stirred for 30 mins. It was warmed to 20 °C and stirred for 1 hour.
  • the mixture was poured into ice-water (200 mL) and extracted with ethyl acetate (300 mL*3). The combined organic phase was washed with brine (100 mL*2), dried over anhydrous Na 2 SC>4, filtered and concentrated in vacuum.
  • the mixture was heated to 80°C for 5 hours under N 2 .
  • the mixture was cooled to 25 °C and poured into ice-water (250 mL).
  • the aqueous phase was extracted with ethyl acetate (300 mL * 3), the combined organic phase was washed with brine (200 mL * 2), dried with anhydrous Na 2 SC>4, filtered and concentrated in vacuum.
  • Step 9 isopropyl 2-(benzyloxy)-8-(bromomethyl)-5.5-dimethyl-6.7.8.9-tetrahvdro-5H- pyrrolo[2.3-b:5.4-c'ldipyridine-8-carboxylate.
  • 2-(6-(benzyloxy)-lH-pyrrolo[2,3- b]pyridin-3-yl)-2-methylpropan-l -amine 400 mg, 1.35 mmol
  • propan-2-ol (10 mL) was added HCl/dioxane (4 M, 405 ⁇ ) in one portion at 20°C under N 2 .
  • Step 10 isopropyl 2-(benzyloxy)-5.5-dimethyl-5.6.7.10-tetrahvdropyrido[3'.2':4.51pyrrolo[2.3- dl azepine-9-carboxylate.
  • Step 1 7-(tert-butyl) 9-isopropyl 2-(benzyloxy)-5.5-dimethyl-5.10- dihvdropyrido[3'.2':4.51pyrrolo[2.3-dlazepine-7.9(6H)-dicarboxylate.
  • Step 2 7-(tert-butyl) 9-isopropyl 5.5-dimethyl-2-oxo-2.5.6.10- tetrahvdropyrido[3'.2':4.51pyrrolo[2.3-dlazepine-7.9(lH)-dicarboxylate.
  • Step 3 isopropyl 5.5.7-trimethyl-2-(((trifluoromethyl)sulfonyl)oxy)-5.6.7.10- tetrahvdropyridor3'.2':4.51pyrrolor2.3-dlazepine-9-carboxylate.
  • Step 4 7-(tert-butyl) 9-isopropyl 5.5-dimethyl-5.10-dihvdropyridor3'.2':4.51pyrrolor2.3- dlazepine-7.9(6H)-dicarboxylate.
  • Step 1 2-(6-methoxy-lH-pyrrolo[2.3-blpyridin-3-yl)-2-methylpropanenitrile.
  • a solution of 3-(2- cyanopropan-2-yl)-lH-pyrrolo[2,3-b]pyridine 7-oxide (Intermediate 2, product from Step 6, 320 mg, 1.6 mmol) and Me 2 S0 4 (160.4 mg, 1.3 mmol) in MeCN (5 mL) was refluxed for 12 hours at 80°C with stirring. After cooling down to 20 °C, NaOMe (103 mg, 1.91 mmol) in MeOH (5 mL) was added to the mixture. The mixture was stirred for 12 hours at 80 °C. The reaction mixture was concentrated under reduced pressure.
  • Step 1 tert-butyl 3-(cvanomethyl)-lH-pyrrolor3.2-clpyridine-l-carboxylate.
  • 2- (lH-pyrrolo[3,2-c]pyridin-3-yl)acetonitrile (Intermediate 7, 710 mg, 4.5 mmol) and di-tert-butyl dicarbonate (1.28 g, 5.9 mmol) in DCM (30 mL) was added Et 3 N (457.1 mg, 4.5 mmol) and DMAP (55.2 mg, 452 umol). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated at low pressure. The residue was purified by column chromatography
  • reaction mixture was cooled to 0 °C and quenched cautiously with wet THF (contains 10% of H 2 0) until gas evolution had ceased.
  • the resulting mixture was filtered through Celite ® and the filtrate was concentrated under reduced pressure to afford the title compound (610 mg), which was used into the next step without further purification.
  • Step 5 ethyl 2-benzyl-10.10-dimethyl-2.8.9.10-tetrahvdropyrido[3'.4':4.51pyrrolo[2.3-dlazepine- 6-carboxylate.
  • Step 1 isopropyl 2-benzyl-10.10-dimethyl-2.8.9.10-tetrahvdropyrido[3'.4':4.51pyrrolo[2.3- dl azepine-6-carboxylate.
  • ethyl 2-benzyl-8-(3,4-difluorobenzoyl)-10,10- dimethyl-2,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6-carboxylate (Intermediate 9, 120 mg, 232.8 ⁇ ) in i-PrOH (2 mL) was added K 2 C0 3 (9 mg, 698 ⁇ ), and stirred at 80 °C for 4 hours. The reaction mixture was cooled to 20 °C, filtered and concentrated to afford the title compound (100 mg, crude) as yellow solid.
  • Step 2 isopropyl 2-benzyl-8-(3.4-difluorobenzoyl)-10.10-dimethyl-2.8.9.10- tetrahvdropyridor3'.4':4.51pyrrolor2.3-dlazepine-6-carboxylate.
  • Step 1 isopropyl 2-benzyl-5.5-dimethyl-1.2.4a.5.6.7.10.10a- octahvdropyrido[4'.3':4.51pyrrolo[2.3-dlazepine-9-carboxylate.
  • Step 2 7-(tert-butyl) 9-isopropyl 2-benzyl-5.5-dimethyl-2.4a.5.6.10.10a- hexahvdropyrido[4'.3':4.51pyrrolo[2.3-dlazepine-7.9(lH)-dicarboxylate.
  • Step 3 7-(tert-butyl) 9-isopropyl 5.5-dimethyl-2.3.4.4a.5.6.10.10a- octahvdropyridor4'.3':4.51pyrrolor2.3-dlazepine-7.9(lH)-dicarboxylate.
  • Step 4 isopropyl 5.5-dimethyl-5.6.7.10-tetrahvdropyridor4'.3':4.51pyrrolor2.3-dlazepine-9- carboxylate.
  • To a solution of 7-(tert-butyl) 9-isopropyl 5,5-dimethyl-2,3,4,4a,5,6,l 0,10a- octahydropyrido[4',3':4,5]pyrrolo[2,3-d]azepine-7,9(lH)-dicarboxylate (210.7 mg, 496.6 ⁇ ) in xylene (10 mL) was added Pd/C (327.9 mg, 10%), and stirred at 140 °C for 10 hours. The reaction mixture was filtered and the filter was concentrated to give the title compound (88.7 mg, crude) as a black oil which was used without purification.
  • Step 1 8-(tert-butyl) 6-ethyl 2-benzyl-10.10-dimethyl-9.10-dihvdropyridor3'.4 l :4.51pyrrolor2.3- dlazepine-6.8(2H)-dicarboxylate.
  • Step 2 8-(tert-butyl) 6-ethyl 10.10-dimethyl-9.10-dihvdropyridor3'.4 l :4.51pyrrolor2.3-dlazepine- 6.8(5H)-dicarboxylate.
  • 8-(tert-butyl) 6-ethyl 2-benzyl-10,10-dimethyl-9,10- dihydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6,8(2H)-dicarboxylate 1.2 g, 2.52 mmol
  • EtOAc 25 mL
  • Step 3 8-(tert-butoxycarbonyl)-10.10-dimethyl-5.8.9.10-tetrahvdropyridor3 l .4 l :4.51pyrrolor2.3- dlazepine-6-carboxylic acid.
  • 8-(tert-butyl) 6-ethyl 10,10-dimethyl-9,10- dihydropyrido[3',4':4,5]pyrrolo[2,3-d]azepine-6,8(5H)-dicarboxylate (731 mg, 1.9 mmol) in H 2 0 (6 mL) and EtOH (20 mL) was added KOH (319.2 mg, 5.69 mmol) under N 2 at 25 °C.
  • Step 4 tert-butyl 6-(isopropyl(methyl)carbamoyl)-10.10-dimethyl-9.10- dihvdropyrido[3'.4':4.51pyrrolo[2.3-dlazepine-8(5H)-carboxylate.
  • Compound 1 isopropyl 7-(3.4-difluorobenzoyl)-5.5-dimethyl-5.6.7.10- tetrahvdropyridor3'.2':4.51pyrrolor2.3-dlazepine-9-carboxylate as the hydrochloric acid salt.
  • Step 1 isopropyl 7-(3.4-difluorobenzoyl)-5.5-dimethyl-5.6.7.10- tetrahvdropyrido[3'.2':4.51pyrrolo[2.3-dlazepine-9-carboxylate.
  • Step 2 isopropyl 7-(3.4-difluorobenzoyl)-5.5-dimethyl-5.6.7.10- tetrahvdropyrido[3'.2':4.51pyrrolo[2.3-dlazepine-9-carboxylate as the hydrochloric acid salt.
  • Compound 2 isopropyl 7-(3.4-difluorobenzoyl)-5.5-dimethyl-2-oxo-1.2.5.6.7.10- hexahvdropyrido[3'.2':4.51pyrrolo[2.3-dlazepine-9-carboxylate.
  • Step 1 isopropyl 2-(benzyloxy)-7-(3.4-difluorobenzoyl)-5.5-dimethyl-5.6.7.10- tetrahvdropyridor3'.2':4.51pyrrolor2.3-dlazepine-9-carboxylate.
  • Step 2 isopropyl 7-(3.4-difluorobenzoyl)-5.5-dimethyl-2-oxo-1.2.5.6.7.10- hexahvdropyrido[3'.2':4.51pyrrolo[2.3-dlazepine-9-carboxylate.
  • Compound 3 isopropyl 8-(3.4-difluorobenzoyl)-10.10-dimethyl-5.8.9.10- tetrahvdropyridor2'.3':4.51pyrrolor2.3-dlazepine-6-carboxylate.
  • the title compound was prepared in a manner analogous to Compound 2, using isopropyl 2- (benzyloxy)-10,10-dimethyl-5, 8,9,10-tetrahy dropyrido[2',3':4,5]pyrrolo[2,3-d]azepine-6- carboxylate (Intermediate 4) instead of isopropyl 7-((ll-methyl)(ll -oxidanyl)boranyl)-2- (benzyloxy)-5,5-dimethyl-5,6,7, 10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-9- carboxylate (Intermediate 2) in Step 1.
  • the title compound (12 mg) was obtained as yellow solid.
  • Compound 8. isopropyl 8-(3-fluorobenzoyl)-10.10-dimethyl-5.8.9.10- tetrahvdropyridor3'.4':4.51pyrrolor2.3-dlazepine-6-carboxylate.
  • Step 1 isopropyl 2-benzyl-10.10-dimethyl-2.8.9.10-tetrahvdropyridor3'.4':4.51pyrrolor2.3- dl azepine-6-carboxylate.
  • 2-(5-benzyl-3a,4,5,6,7,7a-hexahydro-lH-pyrrolo[3,2- c] pyridin-3-yl)-2-methylpropan-l-amine (Intermediate 8, Product from Step 4, 800 mg, 2.8 mmol) in dioxane (5 mL) was added HC1/ dioxane (4 M, 1.4 mL) in one portion at 20 °C under N 2 .
  • Step 2 isopropyl 2-benzyl-8-(3-fluorobenzoyl)-10.10-dimethyl-2.8.9.10- tetrahvdropyridor3'.4':4.51pyrrolor2.3-dlazepine-6-carboxylate.
  • 3-fluorobenzoic acid 53.9 mg, 385.1 ⁇
  • DIPEA 66.3 mg, 513.5 ⁇
  • HATU 146.4 mg, 385.1 ⁇
  • Step 3 isopropyl 8-(3-fluorobenzoyl)-10.10-dimethyl-5.8.9.10- tetrahvdropyrido[3'.4':4.51pyrrolo[2.3-dlazepine-6-carboxylate.
  • isopropyl 2- benzyl-8-(3-fluorobenzoyl)-10,10-dimethyl-2,8,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[2,3- d] azepine-6-carboxylate 70 mg, 136.8 ⁇
  • EtOAc 2 mL
  • Pd(OH) 2 38.4 mg, 20%
  • the suspension was degassed under vacuum and purged with H 2 several times and stirred under H 2 (15 psi) at 20 °C for 1.5 hours.
  • the reaction mixture was filtered and concentrated in vacuum.
  • the residue was purified by prep-HPLC (neutral conditions).
  • the solution was concentrated in vacuum and lyophilization to afford 109 (18.7 mg, 29.3%) as yellow solid.
  • Compound 10 isopropyl 8-(3-chlorobenzoyl)-10.10-dimethyl-5.8.9.10- tetrahvdropyrido[3'.4':4.51pyrrolo[2.3-dlazepine-6-carboxylate.
  • Farnesoid X Receptor (FXR) assay is a cell based reporter assay sold as a kit by Indigo Biosciences (cat# IB00601-32). In brief, compounds were diluted at 2x final concentration in Cell Recovery Medium (CRM). Indigo's FXR reporter cells were thawed and 100 ⁇ added per well to 96-well plates. Compounds were tested at a top concentration of 100 ⁇ with an 8 point dilution curve, 3-fold dilution between points. Chenodeoxycholic acid (CDCA) was used as positive control, top concentration of 1200 ⁇ . 100 ⁇ of diluted compounds added to each cell seeded well.
  • CCM Cell Recovery Medium
  • Treated cells were then incubated for 22 - 25 hours at 37°C, 5% CO 2 . The next day, media was removed from cells and Luciferase Detection Reagent added to wells (100 ⁇ / well). Assay plate was allowed to rest for 25 minutes at room temperature without shaking.
  • FXR agonists were tested in a cell-free FXR co-activation assay.
  • the FXR activation assay was performed using the LanthaScreen® TR-FRET FXR Coactivator Kit (ThermoFisher Scientific) to determine EC50s.
  • 20 reactions were carried out in 384-well plates containing various concentrations of agonist, 5nM FXR/LBD, 500 nM Fluorescein and 5 nM AntiGST Antibody. Plates were incubated at 37°C for 90 min. Changes in fluorescence were monitored using the Victor X3 multilabel plate reader (PerkinElmer). All binding curves were generated by plotting emission ratios vs. ligand concentrations, and % activation is reported as a function of % CDCA activation. Results for certain exemplary compounds of the disclosure are shown in Table 1.

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Abstract

La présente invention concerne des modulateurs du récepteur farnésoïde X. L'invention concerne également des procédés de préparation et d'utilisation de ces modulateurs.
PCT/US2017/018292 2016-02-19 2017-02-17 Modulateurs de fxr et leurs procédés d'utilisation WO2017143134A1 (fr)

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
WO2021014349A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021014350A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement combiné de maladies hépatiques à l'aide d'agonistes de fxr
WO2021044287A1 (fr) 2019-09-03 2021-03-11 Novartis Ag Traitement de maladie ou de trouble hépatique comprenant des antagonistes de récepteur actrii
WO2021053618A1 (fr) 2019-09-19 2021-03-25 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021064575A1 (fr) 2019-09-30 2021-04-08 Novartis Ag Traitement comprenant l'utilisation d'agonistes de fxr
WO2021127466A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Polythérapie de maladies hépatiques à l'aide d'inhibiteurs d'intégrine
WO2022101853A1 (fr) 2020-11-16 2022-05-19 Novartis Ag Procédé de détermination de la fibrose hépatique

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US20040023947A1 (en) * 2002-05-24 2004-02-05 X-Ceptor Therapeutics Inc. Azepinoindole and pyridoindole derivatives as pharmaceutical agents
US20050054634A1 (en) * 2002-05-24 2005-03-10 Brett Busch Azepinoindole derivatives as pharmaceutical agents
US20070015746A1 (en) * 2003-07-23 2007-01-18 X-Ceptor Therapeutics Inc. Azepine derivaties as pharmaceutical agents
US20090163474A1 (en) * 2007-10-19 2009-06-25 Wyeth FXR Agonists for the Treatment of Nonalcoholic Fatty Liver and Cholesterol Gallstone Diseases
US20090203577A1 (en) * 2005-12-15 2009-08-13 Exelixis, Inc. Azepinoindole Derivatives As Pharmaceutical Agents
US20110039824A1 (en) * 2008-09-26 2011-02-17 Wyeth 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate nuclear receptor inhibitors
WO2015138986A1 (fr) * 2014-03-13 2015-09-17 Salk Institute For Biological Studies Agonistes fxr et leurs procédés de fabrication et d'utilisation

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US20040023947A1 (en) * 2002-05-24 2004-02-05 X-Ceptor Therapeutics Inc. Azepinoindole and pyridoindole derivatives as pharmaceutical agents
US20050054634A1 (en) * 2002-05-24 2005-03-10 Brett Busch Azepinoindole derivatives as pharmaceutical agents
US20070015746A1 (en) * 2003-07-23 2007-01-18 X-Ceptor Therapeutics Inc. Azepine derivaties as pharmaceutical agents
US20090203577A1 (en) * 2005-12-15 2009-08-13 Exelixis, Inc. Azepinoindole Derivatives As Pharmaceutical Agents
US20090163474A1 (en) * 2007-10-19 2009-06-25 Wyeth FXR Agonists for the Treatment of Nonalcoholic Fatty Liver and Cholesterol Gallstone Diseases
US20110039824A1 (en) * 2008-09-26 2011-02-17 Wyeth 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate nuclear receptor inhibitors
WO2015138986A1 (fr) * 2014-03-13 2015-09-17 Salk Institute For Biological Studies Agonistes fxr et leurs procédés de fabrication et d'utilisation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021014349A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021014350A1 (fr) 2019-07-23 2021-01-28 Novartis Ag Traitement combiné de maladies hépatiques à l'aide d'agonistes de fxr
WO2021044287A1 (fr) 2019-09-03 2021-03-11 Novartis Ag Traitement de maladie ou de trouble hépatique comprenant des antagonistes de récepteur actrii
WO2021053618A1 (fr) 2019-09-19 2021-03-25 Novartis Ag Traitement comprenant des agonistes de fxr
WO2021064575A1 (fr) 2019-09-30 2021-04-08 Novartis Ag Traitement comprenant l'utilisation d'agonistes de fxr
WO2021127466A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Polythérapie de maladies hépatiques à l'aide d'inhibiteurs d'intégrine
WO2022101853A1 (fr) 2020-11-16 2022-05-19 Novartis Ag Procédé de détermination de la fibrose hépatique

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